Benzoxazoles with PDE-inhibiting activity

ABSTRACT

Compounds of formula I                    
     in which R1, R2, R3 and A have the meaning set forth in the specification, are selective cyclic nucleotide phosphodiesterase (PDE) inhibitors useful as therapeutics in human and veterinary medicine. They are distinguished by low toxicity, good enteral absorption (high bioavailability), a wide therapeutic breadth and absence of significant side effects.

This application is a national stage entry under 35 U.S.C. 371 ofPCT/EP99/04451, filed Jun. 26, 1999 and published in English.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel benzoxazoles which are employed in thepharmaceutical industry for the preparation of medicaments.

1. Known Technical Background

International Patent Application WO 96/11917 describes substitutedbenzoxazoles as cyclic nucleotide phosphodiesterase inhibitors of type4. U.S. Pat. No. 4,405,633 and European Patent Application EP-A-127 066propose substituted benzoxazoles as agents for the prevention andtreatment of asthma.

2. Description of the Invention

It has now been found that the benzoxazoles described below in greaterdetail, which differ from the previously published compounds by adifferent type of substitution, have surprising and particularlyadvantageous properties.

The invention thus relates to compounds of the formula I

in which

R1 is 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxyor completely or predominantly fluorine-substituted 1-4C-alkoxy,

R2 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or1-4C-alkoxy-1-4C-alkyl,

R3 is hydrogen, hydroxyl, nitro, cyano, ethynyl, carboxyl, 1-4C-alkoxyor 1-4C-alkoxycarbonyl,

A is B, —CH(R4)—, >C═O or >C═N—R5, where

B is oxygen (—O—), imino (—NH—), sulfinyl (—S(O)—), sulfonyl (—S(O)₂—)or carbonylimino (—C(O)NH—) and

R4 is hydroxyl, carboxyl, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, hydroxyaminocarbonyl (—C(O)NHOH) or1-4C-alkoxyaminocarbonyl,

R5 is hydroxyl or 1-4C-alkylcarbonyloxy,

and the salts of these compounds.

1-7C-Alkyl represents straight-chain or branched alkyl radicals having 1to 7 carbon atoms. Examples which may be mentioned are the heptyl,isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpenty), neohexyl(3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl(2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl,isopropyl, ethyl and methyl radicals.

1-6C-Alkoxy represents a radical which, in addition to the oxygen atom,contains a straight-chain or branched alkyl radical having 1 to 6 carbonatoms. Alkoxy radicals having 1 to 6 carbon atoms which may be mentionedare, for example, the hexyloxy, isohexyloxy (4-methylpentyloxy),neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy(3-methylbutoxy), neopentyioxy (2,2-dimethylpropoxy), butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxyradicals.

3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexyl-methoxy and cycloheptylmethoxy, of whichcyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy arepreferred.

Completely or predominantly fluorine-substituted 1-4C-alkoxy which maybe mentioned are, for example, the 2,2,3,3,3-pentafluoropropoxy, theperfluoroethoxy and the 1,2,2-trifluoroethoxy radicals, in particularthe 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, thetrifluoromethoxy and preferably the difluoromethoxy radicals.

3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl andcyclopentyl are preferred.

3-7C-Cycloalkylmethyl represents a methyl radical which is substitutedby one of the abovementioned 3-7C-cycloalkyl radicals. The3-5C-cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl andcyclopentylmethyl may preferably be mentioned.

1-4C-Alkoxy-1-4C-alkyl represents one of the abovementioned 1-4C-alkylradicals which is substituted by one of the abovementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the methoxymethyl and themethoxyetnyl radicals and the butoxyethyl radical.

1-4C-Alkoxycarbonyl represents a carbonyl group to which is bonded oneof the abovementioned 1C-alkoxy radicals. Examples which may bementioned are the methoxycarbonyl (CH₃O—C(O)—) and the ethoxycarbonyl(CH₃CH₂O—C(O)—) radicals.

In addition to the carbonyl group, mono- or di-14C-alkylaminocarbonylradicals contain one of the abovementioned mono- or di-14C-alkylaminoradicals. Examples which may be mentioned are the N-methyl, theN,N-dimethyl, the N-ethyl, the N-propyl, the N,N-diethyl and theN-isopropylaminocarbonyl radicals.

A 1-4C-alkylaminocarbonyl radical which may be mentioned is, forexample, the methoxyaminocarbonyl radical (—C(O)NHOCH₃).

1-4C-Alkylcarbonyloxy represents a carbonyloxy group to which is bondedone of the abovementioned 1-4C-alkyl radicals. An example which may bementioned is the acetoxy radical (CH₃C(O)—O—).

Suitable salts of compounds of the formula I—depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerable saltsof the inorganic and organic acids customarily used in pharmacy. Thosesuitable are, on the one hand, water-soluble and water-insoluble acidaddition salts with acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, aceticacid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

On the other hand, salts with bases are also suitable. Examples of saltswhich bases which may be mentioned are alkali metal (lithium, sodium,potassium) or calcium, aluminum, magnesium, titanium, ammonium,meglumine or guanidinium salts, where here too the bases are employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts which can initially be obtained asprocess products, for example in the preparation of the compoundsaccording to the invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

It is known to the person skilled in the art that the compoundsaccording to the invention and also their salts, when they are isolated,for example, in crystalline form, can contain various amounts ofsolvents. The invention therefore also includes all solvates and inparticular all hydrates of the compounds of the formula I, and also allsolvates and in particular all hydrates of the salts of the compounds ofthe formula I.

Compounds of the formula I to be emphasized are those in which

R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy or completely or predominantlyfluorine-substituted 1-2C-alkoxy,

R2 is 1-4C-alkyl, 3-5C-cycloalkyl, 3-5C-cycloalkylmethyl or1-2C-alkoxy-1-2C-alkyl,

R3 is hydroxyl, cyano, carboxyl, 1-2C-alkoxy or 1-2C-alkoxycarbonyl,

A is B, —CH(R4)—, >C═O or >C═N—R5, where

B is oxygen (—O—), sulfinyl (—S(O)—), sulfonyl (—S(O)₂—) orcarbonylimino (—C(O)NH—) and

R4 is hydroxyl, carboxyl, 14C-alkoxycarbonyl or aminocarbonyl,

R5 is hydroxyl or 1-4C-alkylcarbonyloxy,

and the salts of these compounds.

Compounds of the formula I particularly to be emphasized are those inwhich

R1 is 1-4C-alkoxy,

R2 is 1-4C-alkyl or 3-5C-cycloalkyl,

R3 is hydroxyl, cyano or methoxy,

A is B, —CH(R4)— or >C═O, where

B is oxygen (—O—) or sulfonyl (—S(O)₂—),

R4 is hydroxyl, carboxyl, methoxycarbonyl or aminocarbonyl,

and the salts of these compounds.

One embodiment of the particularly preferred compounds of the formula Iare those in which

R1 is 1-4C-alkoxy,

R2 is 1-4C-alkyl or 3-5C-cycloalkyl,

R3 is hydroxyl, cyano or methoxy,

A is B or —CH(R4)—, where

B is oxygen (—O—) or sulfonyl (—S(O)₂—),

R4 is carboxyl, methoxycarbonyl or aminocarbonyl,

and the salts of these compounds.

Preferred compounds of the formula I are those in which

R1 is 1-4C-alkoxy,

R2 is 1-4C-alkyl,

R3 is cyano,

A is B, —CH(R4)— or >C═O, where

B is oxygen (—O—) and

R4 is hydroxyl, carboxyl, methoxycarbonyl or aminocarbonyl,

and the salts of these compounds.

Particularly preferred compounds of the formula I are those in which

R1 is methoxy,

R2 is methyl or isopropyl,

R3 is cyano,

A is B, —CH(R4)— or >C═O,

B is oxygen (—O—) and

R4 is hydroxyl, carboxyl, methoxycarbonyl or aminocarbonyl,

and the salts of these compounds.

One embodiment of the particularly preferred compounds of the formula Iare those in which

R1 is methoxy,

R2 is methyl or isopropyl,

R3 is cyano,

A is oxygen (—O—),

and the salts of these compounds.

The compounds of the formula I can be present—if A is —CH(R4)— as cis ortrans isomers. The invention therefore includes both all pure cis andtrans isomers and their mixtures in any mixing ratio. The pure cisisomers are preferred in this connection.

The invention further relates to processes for the preparation of thecompounds of the formula I and their salts.

Compounds of the formula I in which A is —CH(R4)—, R1, R2 and R3 havethe meanings indicated above and R4 is carboxyl can be prepared, forexample, by hydrolyzing corresponding compounds of the formula I inwhich, is —CH(R4)— and R4 is alkoxycarbonyl and, if desired, thenconverting compounds of the formula I obtained into their salts, orconverting salts of the compounds of the formula I obtained into thefree compounds.

If desired, further compounds of the formula I can be converted intoother compounds of the formula I by derivatization (in particular of theradicals R3 and R4) in a manner known to the person skilled in the art.In this manner, for example, compounds of the formula I in which R1, R2and R3 have the meanings indicated above, A is —CH(R4)— and R4 isaminocarbonyl, mono- or di-alkylaminocarbonyl, alkoxyaminocarbonyl orhydroxyaminocarbonyl, are also accessible.

The hydrolysis of compounds of the formula I in which A is —CH(R4)— andR4 is alkoxycarbonyl is carried out by application of methods known tothe person skilled in the art.

Compounds of the formula I in which A is —CH(R4)—, R1, R2 and R3 havethe meanings indicated above and R4 is alkoxycarbonyl are obtained, forexample, by solvolysis of corresponding compounds of the formula I, inwhich A is

The solvolysis is preferentially carried out in an absolute alcohol as asolvent under acidic conditions in the presence of a mercury salt, suchas, for example, mercury(II) chloride.

Compounds of the formula I, in which A is

and R1, R2 and R3 have the meanings indicated above, can be prepared,for example, from the corresponding compounds of the formula II

by reaction with 2-lithium-2-trimethylsilyl-1,3-dithiane.

The reaction is expediently carried out at low temperatures (preferably−60° to −100° C.) under a protective gas atmosphere in an inert solventsuch as, for example, n-hexane, diethyl ether or tetrahydrofuran ormixtures thereof.

Compounds of the formula II in which R1 and R2 have the abovementionedmeanings and R3 is cyano can be prepared, for example, by application ofknown methods starting from corresponding compounds of the formula III

in which X is the group —CH₂CN, according to reaction scheme 1.

The compounds of the formula III in which R1 and R2 have the meaningsindicated above and X is the group —CH₂CN can be prepared according tothe general reaction scheme 2.

The synthesis of compounds of the formula III is described by way ofexample under “starting compounds”. Further compounds can be preparedanalogously.

The preparation of compounds of the formula V is described, for example,by M. Grossa, F. Wessely in Monatshefte Chemie 1966, 97, 1384-1390.

Compounds of the formula I in which R1 and R2 have the abovementionedmeanings, R3 is hydrogen or cyano and A is —CH(OH)— can be prepared fromcorresponding compounds of the formula II by selective reduction of thecarbonyl group.

The preparation of the keto compounds of the formula II in which R3 iscyano or hydrogen is described in reaction schemes 1 and 3.

Compounds of the formula II in which R1 and R2 have the abovementionedmeanings and R3 is hydrogen are accessible, for example, by addition ofappropriate compounds of the formula III, in which X has the meaninglithium, to 1,4-cyclohexanedione, subsequent elimination of water andselective reduction of the resulting double bond. The1,4-cyclohexanedione is expediently employed in partially protectedform, for example as a monoethylene ketal, and the protective group isremoved again after reaction has taken place (reaction scheme 3).

Compounds of the formula III in which X is lithium are accessible fromcorresponding compounds of the formula III in which X is halogen, inparticular bromine, by metal-halogen exchange.

The reduction of the carbonyl group in compounds of the formula II iscarried out in a manner known to the person skilled in the art,preferably in suitable inert solvents such as 1,2-dimethoxyethane or analcohol such as methanol, using a suitable reductant such as, forexample, sodium borohydride or lithium borohydride.

Compounds of the formula I in which R1 and R2 have the abovementionedmeanings, R3 is cyano, nitro or 1-4C-alkoxycarbonyl and A is oxygen(—O—), imino (—NH—), sulfinyl (—S(O)—) or sulfonyl (—S(O)₂—) can beprepared, for example, from compounds of the formula III in which R1 andR2 have the meanings indicated above and X is —CH₂CN, —CH₂NO₂ or—CH₂COOR (R═1-4C-alkyl) by reaction with suitably activated ethers,amines, sulfines or sulfones.

An The reactions are preferably carried out in anhydrous inert solventssuch as, for example, THF, DMF, DMSO or HMPT or mixtures thereof and,depending on reactivity of the reagents employed, at temperaturesbetween −30° C. and 100° C.

After deprotonation of the —CH₂CN, —CH₂NO₂ or the —CH₂COOR(R═1-4C-alkyl) group by a suitable base, ring formation is carried outby reaction with an ether, amine, sulfine or sulfone provided withsuitable leaving groups. Suitable leaving groups which may be mentionedare halogen, in particular chlorine and bromine, and reactive esterifiedhydroxyl groups (e.g. the toluenesulfonyloxy group).

Suitably activated ethers (1), amines (2), sulfines (3) and sulfones (4)which suggest themselves are, for example,bis[2-(toluene-4-sulfonyloxy)ethyl]ether (1),N-benzyl-bis[2-(toluene-4-sulfonyloxy)-ethyl]amine (2),bis[2-(toluene-4-sulfonyloxy)ethyl]sulfine (3) and bis(2-chloroethyl)sulfone (4), (1) can be prepared according to C. Almensa, A. Moyano, F.Serratosa, Tetrahedron 1992, 48, 1497-1506, (2) or (3) can be preparedfrom the corresponding bis-hydroxyl compounds,N-benzyl-bis(2-hydroxyethyl)-amine (Mamaew, Schischkin, J. Org. Chem.(USSR), engl. Transl. 1966, 2, 584) or bis(2-hydroxyethyl) sulfine(Price, Bullit, J. Org. Chem. 1947, 12, 277) by ditosylation.

The protective group of the amine (2) temporarily introduced can beremoved again after ring formation has taken place. Bis(2-chloroethyl)sulfone (4) is commercially obtainable.

Compounds of the formula III in which R1 and R2 have the meaningsindicated above and X is —CH₂COOR can be prepared, for example, byhydrolysis and subsequent esterification of the corresponding compoundsof the formula III in which X is —CH₂CN.

The preparation of compounds of the formula III in which X is —CH₂NO₂ isdescribed, for example, in J. Organic Chemistry, 1988, 53, 2872-2873.

Compounds of the formula I in which R1 and R2 have the meaningsindicated above, R3 is 1-4C-alkoxy and A is oxygen (—O—) can be obtainedfrom the corresponding compounds of the formula I in which R3 ishydroxyl by reaction with suitable alkylating agents.

Compounds of the formula I in which R1 and R2 have the meaningsindicated above, R3 is hydroxyl and A is oxygen (—O—) can be obtained,for example, from compounds of the formula III in which R1 and R2 havethe meanings indicated above and X is lithium by reaction withtetrahydropyran-4-one.

Compounds of the formula I in which R1, R2 and R3 have the meaningsindicated above, A is >C═N—R5 and R5 is hydroxyl can be obtained byreaction of the corresponding compounds of the formula II withhydroxylamine.

By means of further derivatizations of these oxime compounds known tothe person skilled in the art on the basis of his/her expert knowledge,those compounds of the formula I in which A is carbonylimino (byBeckmann rearrangement of the corresponding oxime compounds) or in whichA is >C═N—R5 and R5 is 1-4C-alkylcarbonyloxy (by acylation of thecorresponding oxime compounds) are also accessible.

It is known to the person skilled in the art that it can be necessary inthe case of a number of reactive centers on a starting or intermediatecompound to block one or more reactive centers temporarily by protectivegroups in order to allow a reaction to proceed specifically at thedesired reaction center. A detailed description of the use of a largenumber of proven protective groups is found, for example, in T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

The substances according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuo andrecrystallizing the resulting residue from a suitable solvent orsubjecting it to one of the customary purification methods, such as, forexample, column chromatography on suitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent(e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutylketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, achlorinated hydrocarbon, such as methylene chloride or chloroform, or alow molecular weight aliphatic alcohol such as ethanol or isopropanol),which contains the desired acid or base, or to which the desired acid orbase is then added.

The salts are obtained by filtering, reprecipitating, precipitating witha nonsolvent for the addition salt or by evaporating the solvent. Saltsobtained can be converted by alkalization or by acidification into thefree compounds, which in turn can be converted into salts. In thismanner, pharmacologically intolerable salts can be converted intopharmacologically tolerable salts.

The following examples serve to illustrate the invention in greaterdetail without restricting it. Further compounds of the formula I, whosepreparation is not described explicitly, can also be prepared in ananalogous manner or in a manner familiar to the person skilled in theart per se using customary process techniques.

The abbreviation h stands for hour(s), min. for minute(s), RT for roomtemperature, m.p. for melting point, DMSO for dimethyl sulfoxide, DMFfor dimethylformamide, THF for tetrahydrofuran, HMPT farhexamethylphosphoramide, LDA for lithium diisopropylamide and TLC forthin-layer chromatography.

EXAMPLES FINAL PRODUCTS 1.4a-Cyano-4e-(2-methyl-7-methoxybenzoxazol-4-yl)tetrahydropyran

500 mg (2.47 mmol) of 2-methyl-7-methoxybenzoxazol-4-ylacetonitrile(starting compound A3) are dissolved in 25 ml of absolute THF at RT. 7ml of HMPT are then added and the solution is cooled to −30° C. under aprotective gas atmosphere. Freshly prepared LDA (0.86 ml ofdiisopropylamine and 4.18 ml of a 1.6 M n-butyllithium solution inn-hexane) in 5 ml of absolute THF is then slowly added dropwise to thereaction solution by means of a dropping funnel cooled with dry ice. Themixture is stirred at −30° C. for a further 30 min. After gentle warmingof the reaction solution to −20° C., a solution ofbis[2-(toluene-4-sulfonyloxy)ethyl] ether (1.55 g, 3.73 mmol) [ref. C.Almensa, A. Moyano, F. Serratosa, Tetrahedron 1992, 48, 1497-1506] in 5ml of absolute THF is then slowly injected into the reaction solutionunder a nitrogen countercurrent (−>deep-red coloration of the reactionsolution). The reaction solution is then slowly warmed to about 0° C.and the end of reaction is checked by means of thin-layerchromatography, The reaction solution is poured onto a half-concentratedammonium chloride solution and extracted 5 times with ethyl acetate. Thecombined organic phases are dried over MgSO₄ and concentrated in vacuo.The crude product is purified by chromatography on silica gel (petroleumether/ethyl acetate; 8:2). After recrystallizing from petroleumether/ethyl acetate, the title compound is obtained as colorlesscrystals (130 mg). TLC (silica gel, petroleum ether/ethyl acetate, 6:4);R_(f)−0.40, m.p. 72° C.

2. 4a-Cyano-4e-(2-isopropyl-7-methoxybenzoxazol-4-yl)-tetrahydropyran

550 mg (2.39 mmol) of 2-isopropyl-7-methoxybenzoxazol-4-ylacetonitrile(starting compound A6) are dissolved in 25 ml of absolute THF at RT. 7ml of HMPT are then added and the solution is cooled to −30° C. under aprotective gas atmosphere. Freshly prepared LDA (0.83 ml ofdiisopropylamine and 4.05 ml of a 1.6 M n-butyllithium solution inn-hexane) in 5 ml of absolute THF is then slowly added dropwise to thereaction solution by means of a dropping funnel cooled with dry ice. Themixture is stirred at −30° C. for a further 30 min. After gentle warmingof the reaction solution to −20° C., a solution ofbis[2-(toluene-4-sulfonyloxy)ethyl]ether (1.50 g, 3.61 mmol) [ref. CAlmensa, A. Moyano, F. Serratosa, Tetrahedron 1992, 48, 1497-1506] in 5ml of absolute THF is slowly injected into the reaction solution under anitrogen countercurrent (−>deep-red coloration of the reactionsolution). The reaction solution is then slowly warmed to about 0° C.and the end of reaction is checked by means of thin-layerchromatography. The reaction solution is poured onto a half-concentratedammonium chloride solution and extracted 5 times with ethyl acetate. Thecombined organic phases are dried over MgSO₄ and concentrated in vacuo.The crude product is purified by chromatography on silica gel (petroleumether/ethyl acetate: 9:1). After recrystallizing from petroleumether/ethyl acetate, the title compound is obtained as colorlesscrystals (220 mg). TLC (silica gel, petroleum ether/ethyl acetate, 7:3);R_(f)=0.39, m.p. 156.5° C.

3. 4-Cyano-4-(2-isopropyl-7-methoxybenzoxazol-4-yl)cyclohexanone

0.69 g (1.86 mmol) of methyl5-cyano-5-(2-isopropyl-7-methoxybenzoxazol-4-yl)-2-oxocyclohexanecarboxylate(starting compound A8) is dissolved in 16 ml of DMSO, a solution of 0.73g of NaCl in 2 ml of dist. water is added and the mixture is stirred at140° C. for 8.5 h. After cooling the reaction mixture, it is dilutedwith 80 ml of dist. water and extracted with ethyl acetate, and theorganic phase is separated off, dried over magnesium sulfate andconcentrated to dryness in vacuo. After chromatography, the titlecompound (0.45 g) is obtained as a colorless solid. TLC, silica gel(glass plates), petroleum ether/ethyl acetate (7:3), R_(f)=0.56, m.p.118° C.

4. cis-4-Cyano-4-(2-isopropyl-7-methoxybenzoxazol-4-yl)cyclohexan-1-ol

Sodium borohydride (0.16 g, 4.0 mmol) is introduced with stirring at RTinto a solution of the compound (0.5 g, 1.6 mmol) prepared according toprocedure 3 in absolute methanol (37 ml). The suspension is stirred atRT for 2 h. The reaction mixture is then treated with 1N hydrochloricacid until a pH of 3 is obtained. Distilled water (75 ml) is added tothe reaction solution and it is extracted with ethyl acetate (60 ml, 3times). The combined organic phases are dried over magnesium sulfateand, after filtration, concentrated in vacuo. After chromatography, thetitle compound (0.5 g) is obtained as colorless crystals. TLC, silicagel (glass plates), petroleum ether/ethyl acetate (6:4), R_(f)=0.17,m.p. 116.5° C.

5. Methylcis-4-cyano-(2-isopropyl-7-methoxybenzoxazol-4-yl)cyclohexane-1-carboxylate

The dithiane compound (1.7 g, 4.1 mmol) prepared according to procedureA9 is dissolved in absolute methanol (78 ml) together with mercury(II)chloride (4.6 g, 16.9 mmol) and treated with perchloric acid (70%strength, 3.8 ml). The mixture is heated under reflux for about 1 h.After cooling to RT, the reaction mixture is filtered off with suctionthrough kieselguhr. The filtrate is diluted with ethyl acetate (100 ml)and washed with half-concentrated NaHCO₃ solution (100 ml). The organicphase is further extracted with Na₂SO₃ solution (40% strength, 100 ml),dried over magnesium sulfate, filtered and concentrated in vacuo.Further purification is carried out by means of chromatography andyields the title compound (0.59 g) as a colorless solid. TLC, silica gel(glass plates), petroleum ether/ethyl acetate (7:3), R_(f)=0.51, m.p.83° C.

6.cis-4-Cyano-4-(2-isopropyl-7-methoxybenzoxazol-4-yl)cyclohexane-1-carboxylicacid

The cis-carboxylic acid methyl ester compound (0.49 g, 1.37 mmol)prepared according to procedure 5 is dissolved in a mixture of methanol(21 ml) and ethanol (14 ml) and treated with an aqueous KOH solution(0.63 g of KOH in 7 ml of water) at RT with stirring. It is stirredovernight at RT. The reaction solution is then almost completelyconcentrated in vacuo. The residue is taken up in 1N hydrochloric acid(20 ml) and extracted (3 times) with dichloromethane (30 ml). Thecombined organic phases are dried over magnesium sulfate, filtered offand concentrated in vacuo. The title compound (0.4 g) is obtained ascolorless crystals. TLC, silica gel (glass plates), petroleumether/ethyl acetate (6:4), R_(f)=0.10, m.p. 217.5° C.

7.Cis-4-Cyano-4-(2-isopropyl-7-methoxybenzoxazol-4-yl)cyclohexane-1-carboxamide

The cis-carboxylic acid compound (0.4 g, 1.17 mmol) prepared accordingto procedure 6 is dissolved in thionyl chloride (5.2 ml) and stirredunder reflux for 1 h. The reaction solution is concentrated in vacuo andcoevaporated with toluene (2 times). The residue obtained is dissolvedin absolute toluene (10 ml) and cooled to 0° C. Ammonia gas issubsequently passed through the solution for 10 min., then diethyl ether(10 ml) is added. The resulting colorless precipitate is filtered offand washed with diethyl ether (10 ml). The title compound (0.31 g) isobtained as colorless crystals. TLC, silica gel (glass plates),dichloromethane/methanol 1(9:1), R_(f)=0.55, m.p. 228° C.

Starting Compounds

A1. 2-Acetamido-3-hydroxy-4-methoxybenzaldehyde

2-Amino-3-hydroxy-4-methoxybenzaldehyde (20.0 g, 0.12 mol) [M. Grossa,F. Wessely Monatsh. Chem. 1966, 97, 1384-1390] is dissolved at RT in amixture of pyridine (250 ml) and acetic anhydride (250 ml). The solutionis warmed to 60° C. and stirred for 1.5 h. The reaction solution is thenpoured onto a mixture of ice and half-concentrated aqueous NaCI solution(1:1), extracted with ethyl acetate (5 times), dried over MgSO₄,filtered off and concentrated in vacuo. The title compound is obtainedas a slightly yellow solid (12.5 g) after silica gel chromatography[petroleum ether/ethyl acetate (7:3)]. TLC, silica gel (glass plates),petroleum ether/ethyl acetate (7:3), R_(f)=0.23.

A2. 2-Acetamido-3-hydroxy-4-methoxybenzyl Alcohol

NaBH₄ (550 mg, 14.53 mmol) is slowly added to a solution of2-acetamido-3-hydroxy-4-methoxybenzaldehyde (3.0 g, 14.34 mmol) [M.Grossa, F. Wessely Monatsh. Chem. 1966, 97, 1384-1390] in methanol (80ml). After stirring for 10 minutes, the suspension is poured onto a 0.1N aqueous HCl solution (50 ml) and then extracted with CH₂Cl₂ (3 times).The organic phases are combined, dried over MgSO₄, filtered off andconcentrated in vacuo. The residue obtained is purified by means ofchromatography with pure ethyl acetate and yields the title compound asa colorless solid (2.2 g). TLC, silica gel (glass plates), ethylacetate, R_(f)=0.19.

A3. 2-Methyl-7-methoxybenzoxazol-4-ylacetonitrile

Thionyl chloride (40 ml) is slowly added at 0° C. with stirring to asuspension of 2-acetamido-3-hydroxy-4-methoxybenzyl alcohol (2.5 g, 12.0mmol) and anhydrous CH₂Cl₂ (30 ml). After the reaction mixture haswarmed to RT, it is stirred for 1 h and then stirred at 50° C. for afurther 1.5 h. The reaction solution is concentrated in vacuo and thencoevaporated with toluene (3 times). The residue obtained is dissolvedin a mixture of toluene and DMF (8:1, 45 ml) and added dropwise to asolution of KCN (1.0 g, 15.4 mmol) in 18-crown-6 (4.07 g, 15.4 mmol) andabsolute DMF (55 ml). The reaction solution is stirred overnight at RTand then poured into a half-concentrated aqueous NaCl solution,extracted with ethyl acetate (5 times), dried over MgSO₄, filtered offand concentrated in vacuo. For further purification, the crude productis filtered through a silica gel column [petroleum ether/ethyl acetate(6:4)]. The title compound is obtained as colorless crystals (1.28 g).TLC, silica gel (glass plates), petroleum ether/ethyl acetate (6:4),R_(f=0.32.)

A4. 2-Isopropylamido-3-hydroxy-4-methoxybenzaidehyde

2-Amino-3-hydroxy-4-methoxybenzaldehyde (3.0 g, 17.95 mmol) is dissolvedat RT in a mixture of pyridine (50 ml) and isobutyric anhydride (50 ml).The solution is stirred at 100° C. for 1.5 h. The reaction solution isthen poured onto a mixture of ice and half-concentrated aqueous NaClsolution (1:1), extracted with ethyl acetate (5 times), dried overMgSO₄, filtered off and concentrated in vacuo. The2-isopropylamido-3-isopropylcarbonyloxy-4-methoxybenzaldehyde obtainedis dissolved in absolute methanol (80 ml) and stirred at RT for 1 h withsodium methoxide (14.6 ml of a 5.5 molar solution in absolute methanol).The reaction solution is then poured onto a half-concentrated aqueousammonium chloride solution, extracted with ethyl acetate (5 times),dried over MgSO₄, filtered off and concentrated in vacuo. The titlecompound is obtained after silica gel chromatography [petroleumether/ethyl acetate (7:3)] as a slightly yellow solid (920 mg). TLC,silica gel (glass plates), petroleum ether/ethyl acetate (7:3),R_(f)=0.39.

A5. 2-Isopropylamido-3-hydroxy4-methoxybenzyl alcohol

NaBH₄ (145 mg, 3.83 mmol) is slowly added to a solution of2-isopropylamido-3-hydroxy-4-methoxybenzaldehyde (900 mg, 3.79 mmol) inmethanol (25 ml). After stirring for 10 minutes, the suspension ispoured onto a 0.1 N aqueous HCl solution (20 ml) and then extracted withCH₂Cl₂ (3 times). The organic phases are combined, dried over MgSO₄,filtered off and concentrated in vacuo. The residue obtained is purifiedby means of chromatography with petroleum ether/ethyl acetate (6:4). Thetitle compound is obtained as a colorless solid (820 mg). TLC, silicagel (glass plates), petroleum ether/ethyl acetate (6.4), R_(f)=0.30.

A6. 2-Isopropyl-7-methoxybenzoxazol-4-ylacetonitrile

Thionyl chloride (12 ml) is slowly added at 0° C. with stirring to asuspension of 2-isopropylamido-3-hydroxy-4-methoxybenzyl alcohol (800mg, 3.34 mmol) and anhydrous CH₂Cl₂ (9 ml). After the reaction mixturehas warmed to RT, it is stirred for 1 h and then stirred at 50° C. for afurther 2 h. The reaction solution is concentrated in vacuo and thencoevaporated with toluene (3 times). The residue obtained is dissolvedin DMF (15 ml) and added dropwise to a solution of KCN (282 mg, 4.34mmol) in 18-crown-6 (1.15 g, 4.34 mmol) and absolute DMF (15 ml). Thereaction solution is stirred overnight at RT and then poured into ahalf-concentrated aqueous NaCl solution, extracted with ethyl acetate (5times), dried over MgSO₄, filtered off and concentrated in vacuo. Forfurther purification, the crude product is filtered through a silica gelcolumn [petroleum ether/ethyl acetate (7:3)]. The title compound isobtained as colorless crystals (550 mg). TLC, silica gel (glass plates),petroleum ether/ethyl acetate (7:3), R_(f)=0.50.

A7. Methyl4-cyano-4-(2-isopropyl-7-methoxybenzoxazol-4-yl)heptane-1,7-dicarboxylate

A solution of 0.65 g (2.82 mmol) of2-isopropyl-7-methoxybenzoxazol-4-ylacetonitrile and 0.13 ml of Triton Bin 17 ml of absolute tetrahydrofuran is warmed to 65° C. for 10 min and2.45 ml (31.4 mmol) of methyl acrylate are then added dropwise at 45° C.The solution is heated to reflux for 2 h. After cooling, the solvent isconcentrated in vacuo, and the residue is taken up in 30 ml of ethylacetate and extracted with half-saturated sodium chloride solution. Theorganic phase is dried over magnesium sulfate and concentrated in vacuo.Column chromatography affords the title compound (0.75 g) as a colorlessoil. TLC, silica gel (glass plates), petroleum ether/ethyl acetate(8:2), R_(f)=0.54.

A8. Methyl5-cyano-5-(2-isopropyl-7-methoxybenzoxazol-4-yl)-2-oxocyclohexanecarboxylate

0.21 g (5.20 mmol) of sodium hydride (60% strength in paraffin) is addedto a solution of 0.75 9 (1.86 mmol) of the compound prepared accordingto procedure A7 in 18 ml of 1,2-dimethoxyethane and the mixture isstirred under reflux for 2 h. It is then allowed to cool to RT, 2 ml ofmethanol and then 5 ml of 1N hydrochloric acid are added, and themixture is then treated with 50 ml of distilled water and extracted withethyl acetate. The organic phases are combined, dried over magnesiumsulfate and concentrated to dryness in vacuo. The title compound (0.69g) is obtained as colorless crystals by column chromatography. TLC,silica gel (glass plates), petroleum ether/ethyl acetate (8:2),R_(f)=0.46, m.p. 150° C.

A9.1-(2-Isopropyl-7-methoxybenzoxazol-4-yl)-4-[1,3]dithian-2-ylidenecyclohexanecarbonitrile

2-Trimethylsilyl-1,3-dithiane (2.1 ml, 11.01 mmol) is dissolved inabsolute THF (56 ml) and cooled to −70° C. with stirring. A solution ofn-butyllithium in n-hexane (6.9 ml, 11.1 mmol of a 1.6 molar solution)is then slowly added dropwise under a nitrogen atmosphere by means of aglass syringe and the mixture is stirred at −45° C. for a further 30min. After cooling to −70° C. again, a solution of4-cyano-4-(2-isopropyl-7-methoxybenzoxazol-4-yl)cyclohexanone (1.5 g,4.80 mmol, compound 3) in absolute THE (33 ml) is slowly added dropwise.The mixture is stirred at −70° C. for 1 h and then slowly warmed to RT(about 2 h). For working-up, the reaction solution is diluted with ethylacetate (80 ml) and extracted (2 times) with 0.1 N hydrochloric acid (80ml). The organic phase is dried using magnesium sulfate, filtered offand concentrated in vacuo. Column chromatography affords the titlecompound (1.34 9) as a colorless solid. TLC, silica gel (glass plates),petroleum ether/ethyl acetate (85:15), R_(f)=0.6.

Commercial Utility

The compounds according to the invention have valuable pharmacologicalproperties which make them commercially utilizable. As selective cyclicnucleotide phosphodiesterase (PDE) inhibitors (namely of type 4), theyare suitable, on the one hand, as bronchial therapeutics (for thetreatment of airway obstructions on account of their dilating but alsoon account of their respiratory rate- or respiratory drive-increasingaction) and for the elimination of erectile dysfunction on account ofthe vasodilating action, but on the other hand especially for thetreatment of disorders, in particular of inflammatory nature, e.g. ofthe airways (asthma prophylaxis), of the skin, of the central nervoussystem, of the intestine, of the eyes and of the joints, which aremediated by mediators such as histamine, PAF (plate-activating factor),arachidonic acid derivatives such as leukotrienes and prostaglandins,cytokines, interleukins, chemokines, alpha-, beta- and gamma-interferon,tumor necrosis factor (TNF) or oxygen radicals and proteases. In thiscontext, the compounds according to the invention are distinguished by alow toxicity, a good enteral absorption (high bioavailability), a widetherapeutic breadth and the absence of significant side effects.

On account of their PDE-inhibiting properties, the compounds accordingto the invention can be employed as therapeutics in human and veterinarymedicine, where they can be used, for example, for the treatment andprophylaxis of the following diseases: acute and chronic (in particularinflammatory and allergen-induced) airway disorders of various origin(bronchitis, allergic bronchitis, bronchial asthma, emphysema, COPD);dermatoses (especially of proliferative, inflammatory and allergicnature) such as, for example, psoriasis (vulgaris), toxic and allergiccontact eczema, atopic eczema, seborrheic eczema, lichen simplex,sunburn, pruritus in the anogenital area, alopecia areata, hypertrophicscars, discoid lupus erythematosus, follicular and wide-area pyodermias,endogenous and exogenous acne, acne rosacea and other proliferative,inflammatory and allergic skin disorders; disorders which are based onan excessive release of TNF and leukotrienes, i.e., for example,disorders of the arthritis type (rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis and other arthritic conditions), disordersof the immune system (AIDS, multiple sclerosis), graft versus hostreactions, transplant rejection reactions, symptoms of shock [septicshock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome andARDS (adult respiratory distress syndrome)] and also generalizedinflammations in the gastrointestinal area (Crohn's disease andulcerative colitis); disorders which are based on allergic and/orchronic, faulty immunological reactions in the area of the upper airways(pharynx, nose) and the adjacent regions (paranasal sinuses, eyes), suchas, for example, allergic rhinitis/sinusitis, chronicrhinitis/sinusitis, allergic conjunctivitis and also nasal polyps; butalso disorders of the heart which can be treated by PDE inhibitors, suchas, for example, cardiac insufficiency, or disorders which can betreated on account of the tissue-relaxant action of the PDE inhibitors,such as, for example, erectile dysfunction or colics of the kidneys andof the ureters in connection with kidney stones. In addition, thecompounds according to the invention can be employed for the treatmentof diabetes insipidus and disorders in connection with disturbances ofthe brain metabolism, such as, for example, cerebral senility, seniledementia (Alzheimer's dementia), multiinfarct dementia or alternativelydisorders of the CNS, such as, for example, depressions orarteriosclerotic dementia.

A further subject of the invention is a process for the treatment ofmammals, including humans, that are suffering from one of theabovementioned diseases. The process comprises administering to the sickmammal a therapeutically efficacious and pharmacologically tolerableamount of one or more of the compounds according to the invention.

A further subject of the invention are the compounds according to theinvention for use in the treatment and/or prophylaxis of diseases, inparticular of the diseases mentioned.

The invention likewise relates to the use of the compounds according tothe invention for the production of medicaments which are employed forthe treatment and/or prophylaxis of the diseases mentioned.

Medicaments for the treatment and/or prophylaxis of the diseasesmentioned, which contain one or more of the compounds according to theinvention, are furthermore a subject of the invention.

A further subject of the invention is a commercial product consisting ofa customary secondary packaging, a primary packaging containing themedicament (for example an ampoule or a blister pack) and, if desired,an enclosed leaflet, the medicament showing antagonistic action againstcyclic neocleotide phosphodiesterases of type 4 (PDE4) and leading tothe lessening of the symptoms of diseases which are connected withcyclic nucleotide phosphodiesterases of type 4, and the suitability ofthe medicament for the prophylaxis or treatment of diseases which areconnected with cyclic nucleotide phosphodiesterases of type 4 beingindicated on the secondary packaging and/or on the enclosed leaflet ofthe commercial product, and the medicament containing one or morecompounds of the formula I according to the invention. The secondarypackaging, the primary packaging containing the medicament and theincluded leaflet otherwise correspond to what the person skilled in theart would regard as standard for medicaments of this type.

The medicaments are prepared by processes known per se and familiar tothe person skilled in the art. As medicaments, the compounds accordingto the invention (=active compounds) are either used as such, orpreferably in combination with suitable pharmaceutical auxiliaries, e.g.in the form of tablets, coated tablets, capsules, suppositories,patches, emulsions, suspensions, gels or solutions, the active compoundcontent advantageously being between 0.1 and 95%.

Auxiliaries which are suitable for the desired pharmaceuticalformulations are familiar to the person skilled in the art on the basisof his/her expert knowledge. In addition to solvents, gel-formingagents, ointment bases and other active compound excipients, it ispossible to use, for example, antioxidants, dispersants, emulsifiers,preservatives, solubilizers or permeation promoters.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation. For this, these are either administered directly as a powder(preferably in micronized form) or by nebulization of solutions orsuspensions which contain them. With respect to the preparations andadministration forms, reference is made, for example, to the details inEuropean Patent 163 965.

For the treatment of dermatoses, the compounds according to theinvention are in particular administered in the form of thosemedicaments which are suitable for topical application. For theproduction of the medicaments, the compounds according to the invention(=active compounds) are preferably mixed with suitable pharmaceuticalauxiliaries and processed further to give suitable pharmaceuticalformulations. Suitable pharmaceutical formulations which may bementioned are, for example, powders, emulsions, suspensions, sprays,oils, ointments, fatty ointments, creams, pastes, gels or solutions.

The medicaments according to the invention are produced by processesknown per se. The dosage of the active compounds takes place in theorder of magnitude customary for PDE inhibitors. Thus topicalapplication forms (such as, for example, ointments) for the treatment ofdermatoses contain the active compounds in a concentration of, forexample, 0.1-99%. The dose for administration by inhalation iscustomarily between 0.1 and 3 mg per day. The customary dose in the caseof systemic therapy (p.o. or i.v.) is between 0.03 and 3 mg per kilogramper day.

Biological Investigations

In the investigation of PDE4 inhibition at the cellular level, theactivation of inflammatory cells is of particular importance. An examplewhich may be mentioned is the FMLP(N-formyl-methionyl-leucyl-phenyl-alanine)-induced superoxide productionof neutrophilic granulocytes, which can be measured asluminol-potentiated chemiluminescence [Mc Phail L C, Strum S L, Leone PA and Sozzani S, The neutrophil respiratory burst mechanism. In“Immunology Series” 1992, 57, 47-76; ed. Coffey R G (Marcel Decker,Inc., New York-Basel-Hong Kong)].

Substances which inhibit chemiluminescence and cytokine secretion andthe secretion of proinflammatory mediators in inflammatory cells, inparticular neutrophilic and eosinophilic granulocytes, T lymphocytes,monocytes and macrophages, are those which inhibit PDE4. This isoenzymeof the phosphodiesterase families is particularly represented ingranulocytes. Its inhibition leads to the increase of the intracellularcyclic AMP concentration and thus to the inhibition of cellularactivation. PDE4 inhibition by the substances according to the inventionis thus a central indicator of the suppression in inflammatoryprocesses. (Giembycz M A, Could isoenzyme-selective phosphodiesteraseinhibitors render bronchodilatory therapy redundant in the treatment ofbronchial asthma? Biochem Pharmacol 1992, 43, 2041-2051; Torphy T J etal., Phosphodiesterase inhibitors: new opportunities for treatment ofasthma. Thorax 1991, 46, 512-523; Schudt C et al., Zardaverine: a cyclicAMP PDE 3/4 inhibitor. In “New Drugs for Asthma Therapy”, 379-402,Birkhäuser Verlag Basel 1991; Schudt C et al., Influence of selectivephosphodiesterase inhibitors on human neutrophil functions and levels ofcAMP and Ca; Naunyn-Schmiedebergs Arch Pharmacol 1991, 344, 682-690;Tenor H and Schudt C, Analysis of PDE isoenzyme profiles in cells andtissues by pharmacological methods. In “Phosphodiesterase Inhibitors”,21-40, “The Handbook of Immunopharmacology”, Academic Press, 1996;Hatzelmann A et al., Enzymatic and functional aspects of dual-selectivePDE3I4-inhibitors. In “Phosphodiesterase Inhibitors”, 147-160, “TheHandbook of Immunopharmacology, Academic Press, 1996.)

Inhibition of PDE4 Activity

Methodology

The activity test was carried out according to the method of Bauer andSchwabe, which was adapted to microtiter plates (Naunyn-Schmiedeberg'sArch. Pharmacol. 1980, 311, 193-198). In this test, the PDE reactiontakes place in the first step. In a second step, the resulting5′-nucleotide is cleaved by a 5′-nucleotidase of the snake venom fromCrotalus atrox to give the uncharged nucleoside. In the third step, thenucleoside is separated from the remaining charged substrate onion-exchange columns. The columns are eluted directly into minivials towhich 2 ml of scintillator fluid is additionally added for counting 2 mlof 30 mM ammonium formate (pH 6.0).

The inhibitory values determined for the compounds according to theinvention [inhibitory concentration as -log IC₅₀ (mol/l)] results fromthe following Table A, in which the numbers of the compounds correspondto the numbers of the examples.

TABLE A Inhibition of the PDE4 activity Compound −Iog IC₅₀ 1 6.87 2 7.863 6.96 4 7.77 5 6.46 6 7.69 7 7.65

What is claimed is:
 1. A compound of formula I

in which R1 is 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy,benzyloxy or completely or predominantly fluorine-substituted1-4C-alkoxy, R2 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl,3-7C-cycloalkylmethyl or 1-4C-alkoxy-1-4C-alkyl, R3 is hydrogen,hydroxyl, nitro, cyano, ethynyl, carboxyl, 1-4C-alkoxy or1-4C-alkoxycarbonyl, A is B, —CH(R4)—, >C═O or >C═N—R5, where B isoxygen (—O—), imino (—NH—), sulfinyl (—S(O)—), sulfonyl (—S(O)₂—) orcarbonylimino (—C(O)NH—) and R4 is hydroxyl, carboxyl,1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,hydroxyaminocarbonyl (—C(O)NHOH) or 1-4C-alkoxyaminocarbonyl, R5 ishydroxyl or 1-4C-alkylcarbonyloxy, or a salt thereof.
 2. A compound offormula I as claimed in claim 1, in which R1 is 1-4C-alkoxy,3-5C-cycdoalkoxy or completely or predominantly fluorine-substituted1-2C-alkoxy, R2 is 1-4C-alkyl, 3-5C-cycloalkyl, 3-5C-cycloalkylmethyl or1-2C-alkoxy-1-2C-alkyl, R3 is hydroxyl, cyano, carboxyl, 1-2C-alkoxy or1-2C-alkoxycarbonyl, A is B, —CH(R4)—, >C═O or >C═N—R5, where B isoxygen (—O—), sulfinyl (—S(O)—), sulfonyl (—S(O)₂—) or carbonylimino(—C(O)N H—) and R4 is hydroxyl, carboxyl, 1-4C-alkoxycarbonyl oraminocarbonyl, R5 is hydroxyl or 1-4C-alkyicarbonyloxy, or a saltthereof.
 3. A compound of formula I as claimed in claim 1, in which R1is 1-4C-alkoxy, R2 is 1-4C-alkyl or 3-5C-cycloalkyl, R3 is hydroxyl,cyano or methoxy, A is B, —CH(R4)— or >C═O, where B is oxygen (—O—) orsulfonyl (—S(O)₂—), R4 is hydroxyl, carboxyl, methoxycarbonyl oraminocarbonyl, or a salt thereof.
 4. A compound of formula I as claimedin claim 1, in which R1 is 1-4C-alkoxy, R2 is 1-4C-alkyl, R3 is cyano, Ais B, —CH(R4)— or >C═O, where B is oxygen (—O—) and R4 is hydroxyl,carboxyl, methoxycarbonyl or aminocarbonyl, or a salt thereof.
 5. Acompound of formula I as claimed in claim 1, in which R1 is methoxy, R2is methyl or isopropyl, R3 is cyano, A is B, —CH(R4)— or >C═O, B isoxygen (—O—) and R4 is hydroxyl, carboxyl, methoxycarbonyl oraminocarbonyl, or a salt thereof.
 6. A compound of formula I as claimedin claim 1, in which R1 is methoxy, R2 is methyl isopropyl, R3 is cyano,A is oxygen (—O—), or a salt thereof.
 7. A method of treating acondition amenable to treatment with a cyclic nucleotidephosphodiesterase (PDE) inhibitor of type 4 which comprisesadministering an effective amount of a compound of Formula 1 as claimedin claim 1 or a pharmaceutically acceptable salt thereof to a subject inneed of such treatment.
 8. A medicament composition comprising acompound as claimed in claim 1 or a pharmaceutically acceptable saltthereof together with a pharmaceutical auxiliary and/or excipient.
 9. Amethod of compounding a medicament composition for treating an amenableairway disorder by combining a cyclic nucleotide phosphodiesterase (PDE)inhibitor of type 4 with a pharmaceutical auxiliary and/or excipient,wherein the PDE inhibitor is a compound as claimed in claim 1 or apharmacologically acceptable salt thereof.